The present invention relates to a method of making olanzapine including olanzapine salts, and intermediates therefor.
Olanzapine or 2-methyl-4-[4-methyl-1-piperazinyl]-10H-thieno[2,3b][1,5]-benzodiazepine is a pharmaceutically active compound that can be represented by the formula (1).
It was disclosed in EP 454436 and corresponding U.S. Pat. No. 5,229,382 as a useful antipsychotic agent. Olanzapine acts as a serotonin (5-HT2) and dopamine (D1/D2) receptor antagonist with anticholinergic activity. In commercially available final forms, the active substance is marketed as a free base, which is a white to yellow crystalline solid that is insoluble in water.
One synthetic route for making olanzapine starts from “des-methylpiperazine olanzapine precursor” of formula (3), which reacts with piperazine to form a “des-methyl olanzapine precursor” of formula (2) (see Jun-Da Cen, Chinese Journal of Pharmaceuticals 2001, 32(9),391-393). The compound (2) can be methylated to form olanzapine (see U.S. Pat. No. 4,115,568 for such suggestion). The methylation reaction can be carried out using formaldehyde under conditions of Eschweiler-Clarke reaction (see Jun-Da Cen) or by classical methylation agents such as methyl iodide (see WO 04-000847).

This synthetic pathway has the disadvantage that the reaction with piperazine may lead to formation of dimeric impurities and that the methylation with formaldehyde or other methylation agent may lead to side products, e.g. products of multiple methylation. All these contaminants are difficult to remove from the product. Also, methylation agents are, in general, toxic and mutagenic compounds.
An alternative of the above process was suggested in WO 04/000847 and comprises converting the compound (2) into a “formyl-olanzapine precursor” of formula (4) by a reaction with a methyl formate, and converting the compound (4) into olanzapine by a reduction with a metal borohydride.

In comparison with the preceding procedure, the alternate procedure is one step longer and suffers from the same problems in the step of making compound (2). Furthermore, the reported purity of the actually obtained olanzapine product is only 88%, which is not sufficient for pharmaceutical applications.
Purifying olanzapine is generally difficult. So-called “technical grade” olanzapine, which is generally easy to form but is too impure for pharmaceutical use, has been the starting material for several attempts at forming pharmaceutically acceptable olanzapine. In general, these purification techniques, such as a crystallization, lead to irreproducible results as the formation of various olanzapine polymorphs occurs. Other techniques comprise forming a hydrate or a solvate of olanzapine and then converting the purified hydrate/solvate to olanzapine by dehydration or desolvation. But, the dehydration or desolvation usually requires treatment of the hydrate/solvate at an enhanced temperature, which may cause formation of unwanted decomposition products and a lowering the overall purity. Furthermore, the resulted product may still be contaminated with the undesired polymorphic forms as in the case of crystallization.
It would be desirable to have a synthetic route that allowed the formation of olanzapine in a more pure form.